1. Field of the Invention
The described invention relates to the family of mammalian Neuralized (neu) genes, proteins encoded by those genes (Neu), expression patterns of the gene family, their function as a transcriptional regulator, and the proteins with which the Neu family of proteins interacts. Additionally, therapeutic and diagnostic uses for the Neu family of proteins and agents that bind thereto are also provided.
2. Description of the Related Art
Development and functioning of the nervous system requires orchestrated action of thousands of transcriptional regulators. Balance between transcriptional activators and repressors determines the spectrum of expressed genes. The molecular basis of the initial stages of neurogenesis as well as several aspects of neuronal differentiation have been extensively studied. As a result, a variety of transcriptional activators and repressors have been discovered and characterized. Our understanding of these systems and their component interactions, however, is far from complete. Little is known about the molecular mechanisms that support neuronal circuits in developing and mature nervous systems or the molecular mechanisms that coordinate maintenance of the differentiated state.
The process of lateral inhibition prevents neighboring cells from developing into the same type of differentiated cells in flies and in vertebrates. See Tanabe & Jessell, Science, 274:1115-23 (1996). In Drosophila, a group of mutations has been described that shows severe defects in the process of lateral inhibition in the developing nervous system. These neurogenic mutations result in hyperplasia of the neural tissue at the expense of epidermal structures. See Campos-Ortega & Jan, Annu Rev Neurosci, 14:399-420 (1991). The temporal and spatial expression patterns of neu are compatible with its function as a neurogenic gene in Drosophila. The Neu protein is expressed throughout the ectoderm at the time when cell fate is determined and its expression proceeds in neuroblasts. See Boulianne, et al., EMBO J, 10:2975-2983 (1991). neu expression has been detected in actively proliferating neuroblasts in several regions of the central nervous system (CNS) and peripheral nervous system (PNS). Expression of neu in imaginal disc suggests that it is also involved in later stages of development. The neu gene encodes a RING finger (C3HC4) type zinc finger protein. The molecular function of the Drosophila Neu protein is unknown. Interestingly, it was discovered that EST databases contain a homologue of Neu suggesting that a family of Neu-like proteins is present in Drosophila. 
Current studies of the brain development in Drosophila and vertebrates, indicate that many basic molecular and genetic mechanisms involved in neurogenesis are highly conserved. During development of the nervous system, neural cell specification is acquired through the series of progressive restrictive steps. In Drosophila, neural precursors are first specified by proneural genes including basic helix-loop-helix (bHLH) transcription factors of atonal and achaete-scute complex. Simpson, Neuron, 15:739-742 (1995). The process of lateral inhibition, which further restricts the developmental potential of neuroectodermal cells is regulated by neurogenic genes such as Notch, mastermind, big brain, Delta, Enhancer of split, and neuralized. Analysis of the function of these neurogenic loci in the Drosophila embryo has revealed that mutations in any of these genes result in hyperplasia of neural tissue at the expense of epidermal structures and also cause defects in tissues derived from mesoderm and endoderm. Campos-Ortega and Jan, Annu. Rev Neurosci, 14:399-420 (1991); Harentstein et al., Development, 116:1203-1220 (1992). Vertebrate homologues of Notch, Delta and the proneural/neurogenic genes of atonal, achaete-scute, hairy, and Enhancer of Split complex have been identified and recent work, mostly in Xenopus and mouse, suggests that their role in neurogenesis is conserved. Lewis, Curr Opin Neurobiol, 6:3-10 (1996); Kageyama et al., Int J Biochem Cell Biol, 29:1389-1399 (1997); and Beatus, Lendahl, J Neurosci Res 54:125-136 (1998). For example, postnatal Notch signaling affects the elaboration of different body systems and regulates plasticity of cortical postmitotic neurons. Artavanis-Tsakonas et al., Science, 284:770-776 (1999); Redmond et al., Nat Neurosci, 3:30-40 (2000); and Sestan et al., Science, 286:741-746 (1999).
The last few years have brought the identification and characterization of many new key regulators of vertebrate neurogenesis. Recently, a human homologue of Drosophila Neu gene was isolated and its expression in the adult nervous system and in tumors of neuroectodermal origin, such as astrocytomas, was characterized. Nakamura, et al., Oncogene 16(8):1009-1019 (1998). Nakamura and others (1998) hypothesized that h-neu1 plays a role in determination of cell fate in the central nervous system and may act as a tumor suppressor which inactivation could be associated with malignant progression of astrocytic tumors. A homology search in human, rat, and mouse EST databases revealed three new mammalian Neu homologs, suggesting that a family of Neu-like proteins exists in mammals.